Type 2 diabetes is caused by two physiological defects : resistance to insulin action and defects in insulin secretion. Transgenic and knockout technology used to create animal models of type 2 diabetes have had a major impact in the regulation of newly identified molecules implicated in the regulation of glucose homeostasis in vivo.(i) Development of insulin resistance and diabetes in IRS-1 and IRS-2 knockout mice. To understand the molecular basis of type 2 diabetes development, we have generated IRS- 1 and IRS-2 knockout mice (Tamemoto H, et al. Nature 372 : 182-186, 1994 ; Kubota, N., et al., Diabetes, 49 : 1880-1889, 2000). We demonstrated that both of these mice showed insulin resistance. However, while IRS-1 knockout mice remained normal glucose tolerance in which β cells are able to proliferate (Terauchi Y, et al., J Clin Invest 99 : 861-866, 1997), IRS-2 knockout mice developed diabetes in which β cells are not able to proliferate. It is possible that the ability of β cells to
… More proliferate in response to insulin resistance may determine the process for human type 2 diabetes development. We also demonstrated that mice lacking PI3-kinase 85kDa subunit showed increased insulin sensitivity (Terauchi, Y.et al., Nature Genetics 21 : 230-235, 1999).(ii) Mechanisms of obesity-induced insulin resistanceObesity is defined as an excessive accumulation of adipose tissue. We investigated the molecular basis of obesityinduced insulin resistance. First, we studied the molecular mechanism of how thiazolidinedione, a PPAR γ agonist, improves insulin resistance. Administration of TZD into Zucker fa/fa rats resulted in a marked improvement of insulin resistance. Histological examination of adipose tissue revealed a marked increase in the number of smaller adipocytes with a decreased number of larger adipocytes (Okuno, A., et al., J.Clin. Invest. 101 : 1354-1361, 1998). We further generated PPAR γ knockout mice (Kubota N, et al., Mol Cell 4 : 597-609, 1999) and demonstrated that heterozygotes were protected from obesity and insulin resistance under a high-fat diet. Amelioration of insulin resistance in heterozygotes were explained, at least in part, by increased serum leptin concentration. We also demonstrated that, in human, the lower activity PPARg polymorphism, alanine at codn 12, are protected from the development of insulin resistance and diabetes compared the higher one, proline at codon 12 (Hara, K., et al : Biochem.Biophys.Res. Commun. 271 : 212-216, 2000 Less